Antibiotics

20 pages, 1210 KiB

Open AccessEditor’s ChoiceArticle

Association between Antibiotic Consumption and Resistance in Mink Production

by Nanett Kvist Nikolaisen, Mette Fertner, Desiree Corvera Kløve Lassen, Chaza Nazih Chehabi, Amir Atabak Ronaghinia, Mariann Chriél, Vibeke Frøkjær Jensen, Lars Bogø Jensen, Karl Pedersen and Tina Struve

Antibiotics 2022, 11(7), 927; https://doi.org/10.3390/antibiotics11070927 - 9 Jul 2022

Cited by 4 | Viewed by 3244

Abstract

Antibiotic consumption is considered to be a main driver of antibiotic resistant bacteria. Mink breeding follows a distinctive seasonal reproduction cycle, and all of the mink produced in the northern hemisphere are bred, born, and pelted around the same time of year. Some [...] Read more.

Antibiotic consumption is considered to be a main driver of antibiotic resistant bacteria. Mink breeding follows a distinctive seasonal reproduction cycle, and all of the mink produced in the northern hemisphere are bred, born, and pelted around the same time of year. Some of the diseases are age-related, which is reflected in the seasonal variation of antibiotic consumption. The seasonality makes mink a good model for the investigation of the association between antibiotic consumption and resistance. The objectives of this study were (1) to monitor the farm level of antibiotic resistance during one production cycle and (2) to assess the potential associations between antibiotic consumption and resistance. Twenty-four farms were included in this study (Denmark n = 20, Iceland n = 2, and The Netherlands n = 2), following a cohort of animals born in 2018. Staphylococcus delphini and Escherichia coli were isolated from samples of the carcasses and faeces and were collected randomly. The isolates were susceptibility tested and subsequently divided into the sensitive wildtype (WT) and the resistant non-wildtype (NWT) populations. The antibiotic consumption relative to the sampling periods was assessed as having a short-term or a long-term impact, i.e., in two explanatory factors. For both S. delphini and E. coli, a large between-farm variation of NWT profiles was detected. In the final multivariable, generalized linear mixed models, significant associations between NWT isolates and the consumption of specific antibiotics were found: the short-term use of tetracyclines in the growth period was associated with the occurrence of tetracycline NWT E. coli in the growth period (OR: 11.94 [1.78; 89.28]), and the long-term use of macrolide and tetracyclines was associated with the occurrence of erythromycin NWT S. delphini in the weaning period (OR: 18.2 [2.26; 321.36]) and tetracycline NWT S. delphini in the growth period (OR: 8.2 [1.27; 63.31]), respectively. Farms with zero consumption in the study years prior to sampling also had a substantial proportion of NWT isolates, indicating that NWT isolates are persistent and/or widely spread in the environment. Generally, a high occurrence of tetracycline NWTs was observed. NWT isolates with resistance against the most commonly used antibiotics were found on all the farms, stressing the need for routine surveillance and the prudent use of antibiotics. The results offer a preview of the complex relationship between consumption and resistance, demonstrating some significant associations between use and resistance. Moreover, antibiotic-resistant bacteria are present even on farms with no antibiotic consumption over extended periods, and theoretical explanations supported by the data are offered. Full article

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37 pages, 623 KiB

Open AccessEditor’s ChoiceArticle

Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-Infections: A Report of Three Cases and Literature Review

by Richard I. Horowitz and Phyllis R. Freeman

Antibiotics 2022, 11(7), 912; https://doi.org/10.3390/antibiotics11070912 - 7 Jul 2022

Cited by 5 | Viewed by 27852

Abstract

Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission [...] Read more.

Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was, therefore, to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. A total of 25 patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone × 3–4 days and/or 200 mg BID × 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in eight major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just the treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials. Full article

(This article belongs to the Special Issue Antimicrobial Combination Therapy to Treat Difficult-to-Treat Infections: From Bench to the Bedside)

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14 pages, 1187 KiB

Open AccessEditor’s ChoiceArticle

Antibacterial Activity against Clinical Isolates and In Vivo Efficacy of Coralmycins

by Ha-Young Choi, Bo-Min Kim, Young-Rok Kim, Taehui Yang, Sunjoo Ahn, Dongeun Yong, Jin-Hwan Kwak and Won-Gon Kim

Antibiotics 2022, 11(7), 902; https://doi.org/10.3390/antibiotics11070902 - 6 Jul 2022

Cited by 4 | Viewed by 2951

Abstract

Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and [...] Read more.

Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and in vivo efficacy of coralmycins were studied. Coralmycin A showed potent antibacterial activity with an MIC₉₀ of 1 mg/L against 73 clinical methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci isolates, which was 2–8 times higher than the corresponding activities of DH-coralmycin A, vancomycin, daptomycin, and linezolid, and against 73 vancomycin-resistant Enterococcus and Streptococcus pneumoniae isolates, which was 4–16 times higher than the corresponding activities of DH-coralmycin A, daptomycin, and linezolid. Pharmacokinetic analysis after i.v. injection showed that coralmycins have a moderate volume of distribution and moderate-to-high clearance in mice. The coralmycin A and DH-coralmycin A bioavailability values were 61.3% and 11.7%, respectively, after s.c. administration. In a mouse respiratory tract infection model, coralmycin A showed bacteriostatic and bactericidal in vivo efficacies at an s.c. administration of 4 and 100 mg/kg bid, respectively; these efficacies were similar to those of vancomycin at 4 and 20 mg/kg bid, respectively. The present findings indicate that coralmycin A has great potential as a new class of antibiotic for treating infections caused by multidrug-resistant Gram-positive bacteria. Full article

(This article belongs to the Special Issue Discovery and Development of Novel Antibacterial Agents)

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14 pages, 1590 KiB

Open AccessEditor’s ChoiceArticle

Enhanced Antibacterial Activity of Dermaseptin through Its Immobilization on Alginate Nanoparticles—Effects of Menthol and Lactic Acid on Its Potentialization

by Noura Hazime, Yanath Belguesmia, Alexandre Barras, Mohamed Amiche, Rabah Boukherroub and Djamel Drider

Antibiotics 2022, 11(6), 787; https://doi.org/10.3390/antibiotics11060787 - 9 Jun 2022

Cited by 7 | Viewed by 3021

Abstract

Dermaseptin B2 (DRS-B2) is an antimicrobial peptide secreted by Phyllomedusa bicolor, which is an Amazonian tree frog. Here, we show that the adsorption of DRS-B2 on alginate nanoparticles (Alg NPs) results in a formulation (Alg NPs + DRS-B2) with a remarkable antibacterial [...] Read more.

Dermaseptin B2 (DRS-B2) is an antimicrobial peptide secreted by Phyllomedusa bicolor, which is an Amazonian tree frog. Here, we show that the adsorption of DRS-B2 on alginate nanoparticles (Alg NPs) results in a formulation (Alg NPs + DRS-B2) with a remarkable antibacterial activity against Escherichia coli ATCC 8739 and E. coli 184 strains, which are sensitive and resistant, respectively, to colistin. The antibacterial activity, obtained with this new formulation, is higher than that obtained with DRS-B2 alone. Of note, the addition of lactic acid or menthol to this new formulation augments its antibacterial activity against the aforementioned Gram-negative bacilli. The safety of DRS-B2, and also that of the new formulation supplemented or not with a small molecule such as lactic acid or menthol has been proven on the human erythrocytes and the eukaryotic cell line types HT29 (human) and IPEC-1 (animal). Similarly, their stability was determined under the conditions mimicking the gastrointestinal tract with different conditions: pH, temperature, and the presence of digestive enzymes. Based on all the obtained data, we assume that these new formulations are promising and could be suggested, after in vivo approval and completing regulation aspects, as alternatives to antibiotics to fight infections caused by Gram-negative bacilli such as E. coli. Full article

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11 pages, 1182 KiB

Open AccessEditor’s ChoiceArticle

The Urinary Resistome of Clinically Healthy Companion Dogs: Potential One Health Implications

by Tonatiuh Melgarejo, Nathan Sharp, Janina A. Krumbeck, Guangxi Wu, Young J. Kim and Annika Linde

Antibiotics 2022, 11(6), 780; https://doi.org/10.3390/antibiotics11060780 - 8 Jun 2022

Cited by 2 | Viewed by 3397

Abstract

An interdisciplinary approach to antimicrobial resistance (AMR) is essential to effectively address what is projected to soon become a public health disaster. Veterinary medicine accounts for a majority of antimicrobial use, and mainly in support of industrial food animal production (IFAP), which has [...] Read more.

An interdisciplinary approach to antimicrobial resistance (AMR) is essential to effectively address what is projected to soon become a public health disaster. Veterinary medicine accounts for a majority of antimicrobial use, and mainly in support of industrial food animal production (IFAP), which has significant exposure implications for human and nonhuman animals. Companion dogs live in close proximity to humans and share environmental exposures, including food sources. This study aimed to elucidate the AMR-gene presence in microorganisms recovered from urine from clinically healthy dogs to highlight public health considerations in the context of a species-spanning framework. Urine was collected through cystocentesis from 50 companion dogs in Southern California, and microbial DNA was analyzed using next-generation sequencing. Thirteen AMR genes in urine from 48% of the dogs {n=24} were detected. The most common AMR genes were aph(3′)Ia, and ermB, which confer resistance to aminoglycosides and MLS (macrolides, lincosamides, streptogramins) antibiotics, respectively. Antibiotic-resistance profiles based on the AMR genes detected, and the intrinsic resistance profiles of bacterial species, were inferred in 24% of the samples {n=12} for 57 species, with most belonging to Streptococcus, Staphylococcus, and Corynebacterium genera. The presence of AMR genes that confer resistance to medically important antibiotics suggests that dogs may serve as reservoirs of clinically relevant resistomes, which is likely rooted in excessive IFAP antimicrobial use. Full article

(This article belongs to the Special Issue Antibiotic Use in Veterinary)

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29 pages, 1622 KiB

Open AccessEditor’s ChoiceReview

Insights in the Development and Uses of Alternatives to Antibiotic Growth Promoters in Poultry and Swine Production

by Md Ramim Tanver Rahman, Ismail Fliss and Eric Biron

Antibiotics 2022, 11(6), 766; https://doi.org/10.3390/antibiotics11060766 - 2 Jun 2022

Cited by 108 | Viewed by 70809

Abstract

The overuse and misuse of antibiotics has contributed to the rise and spread of multidrug-resistant bacteria. To address this global public health threat, many countries have restricted the use of antibiotics as growth promoters and promoted the development of alternatives to antibiotics in [...] Read more.

The overuse and misuse of antibiotics has contributed to the rise and spread of multidrug-resistant bacteria. To address this global public health threat, many countries have restricted the use of antibiotics as growth promoters and promoted the development of alternatives to antibiotics in human and veterinary medicine and animal farming. In food-animal production, acidifiers, bacteriophages, enzymes, phytochemicals, probiotics, prebiotics, and antimicrobial peptides have shown hallmarks as alternatives to antibiotics. This review reports the current state of these alternatives as growth-promoting factors for poultry and swine production and describes their mode of action. Recent findings on their usefulness and the factors that presently hinder their broader use in animal food production are identified by SWOT (strength, weakness, opportunity, and threat) analysis. The potential for resistance development as well as co- and cross-resistance with currently used antibiotics is also discussed. Using predetermined keywords, we searched specialized databases including Scopus, Web of Science, and Google Scholar. Antibiotic resistance cannot be stopped, but its spreading can certainly be hindered or delayed with the development of more alternatives with innovative modes of action and a wise and careful use of antimicrobials in a One Health approach. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Antibiotic Alternatives in Livestock)

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15 pages, 1598 KiB

Open AccessEditor’s ChoiceArticle

Synergism between the Synthetic Antibacterial and Antibiofilm Peptide (SAAP)-148 and Halicin

by Miriam E. van Gent, Tanny J. K. van der Reijden, Patrick R. Lennard, Adriëtte W. de Visser, Bep Schonkeren-Ravensbergen, Natasja Dolezal, Robert A. Cordfunke, Jan Wouter Drijfhout and Peter H. Nibbering

Antibiotics 2022, 11(5), 673; https://doi.org/10.3390/antibiotics11050673 - 17 May 2022

Cited by 19 | Viewed by 4660

Abstract

Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than [...] Read more.

Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than halicin in killing planktonic bacteria of antimicrobial-resistant (AMR) Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, especially in biologically relevant media, such as plasma and urine, and in 3D human infection models. Surprisingly, SAAP-148 and halicin were equally effective against these bacteria residing in immature and mature biofilms. As their modes of action differ, potential favorable interactions between SAAP-148 and halicin were investigated. For some specific strains of AMR E. coli and S. aureus synergism between these agents was observed, whereas for other strains, additive interactions were noted. These favorable interactions were confirmed for AMR E. coli in a 3D human bladder infection model and AMR S. aureus in a 3D human epidermal infection model. Together, combinations of these two novel antimicrobial agents hold promise as an innovative treatment for infections not effectively treatable with current antibiotics. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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9 pages, 796 KiB

Open AccessEditor’s ChoiceReview

Use of Novel Antibiograms to Determine the Need for Earlier Susceptibility Testing and Administration for New β-Lactam/β-Lactamase Inhibitors in the United States

by Kenneth P. Klinker, Levita K. Hidayat, Eric Wenzler, Joan-Miquel Balada-Llasat, Mary Motyl, C. Andrew DeRyke and Karri A. Bauer

Antibiotics 2022, 11(5), 660; https://doi.org/10.3390/antibiotics11050660 - 14 May 2022

Cited by 6 | Viewed by 5211

Abstract

Antimicrobial resistance is a global public health threat, and gram-negative bacteria, such as Enterobacterales and Pseudomonas aeruginosa, are particularly problematic with difficult-to-treat resistance phenotypes. To reduce morbidity and mortality, a reduction in the time to effective antimicrobial therapy (TTET) is needed, especially among [...] Read more.

Antimicrobial resistance is a global public health threat, and gram-negative bacteria, such as Enterobacterales and Pseudomonas aeruginosa, are particularly problematic with difficult-to-treat resistance phenotypes. To reduce morbidity and mortality, a reduction in the time to effective antimicrobial therapy (TTET) is needed, especially among critically ill patients. The antibiogram is an effective clinical tool that can provide accurate antimicrobial susceptibility information and facilitate early antimicrobial optimization, decrease TTET, and improve outcomes such as mortality, hospital length of stay, and costs. Guidance is lacking on how to validate the susceptibility to new antibacterial agents. Commonly used traditional and combination antibiograms may not adequately assist clinicians in making treatment decisions. Challenges with the current susceptibility testing of new β-lactam/β-lactamase inhibitor combinations persist, impacting the appropriate antibacterial choice and patient outcomes. Novel antibiograms such as syndromic antibiograms that incorporate resistant gram-negative phenotypes and/or minimum inhibitory concentration distributions may assist in determining the need for earlier susceptibility testing or help define an earlier optimal use of the new β-lactam/β-lactamase inhibitors. The purpose of this review is to emphasize novel antibiogram approaches that are capable of improving the time to susceptibility testing and administration for new β-lactam/β-lactamase inhibitors so that they are earlier in a patient’s treatment course. Full article

(This article belongs to the Special Issue Antimicrobial Use, Resistance and Stewardship)

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31 pages, 2279 KiB

Open AccessEditor’s ChoiceReview

The Use of Bacteriophages in Biotechnology and Recent Insights into Proteomics

by Ana G. Abril, Mónica Carrera, Vicente Notario, Ángeles Sánchez-Pérez and Tomás G. Villa

Antibiotics 2022, 11(5), 653; https://doi.org/10.3390/antibiotics11050653 - 13 May 2022

Cited by 20 | Viewed by 12288

Abstract

Phages have certain features, such as their ability to form protein–protein interactions, that make them good candidates for use in a variety of beneficial applications, such as in human or animal health, industry, food science, food safety, and agriculture. It is essential to [...] Read more.

Phages have certain features, such as their ability to form protein–protein interactions, that make them good candidates for use in a variety of beneficial applications, such as in human or animal health, industry, food science, food safety, and agriculture. It is essential to identify and characterize the proteins produced by particular phages in order to use these viruses in a variety of functional processes, such as bacterial detection, as vehicles for drug delivery, in vaccine development, and to combat multidrug resistant bacterial infections. Furthermore, phages can also play a major role in the design of a variety of cheap and stable sensors as well as in diagnostic assays that can either specifically identify specific compounds or detect bacteria. This article reviews recently developed phage-based techniques, such as the use of recombinant tempered phages, phage display and phage amplification-based detection. It also encompasses the application of phages as capture elements, biosensors and bioreceptors, with a special emphasis on novel bacteriophage-based mass spectrometry (MS) applications. Full article

(This article belongs to the Special Issue Frontiers in Phage Therapy)

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20 pages, 1132 KiB

Open AccessEditor’s ChoiceArticle

Antimicrobial Susceptibility of Enterococcus Isolates from Cattle and Pigs in Portugal: Linezolid Resistance Genes optrA and poxtA

by Joana Gião, Célia Leão, Teresa Albuquerque, Lurdes Clemente and Ana Amaro

Antibiotics 2022, 11(5), 615; https://doi.org/10.3390/antibiotics11050615 - 3 May 2022

Cited by 17 | Viewed by 4292

Abstract

Enterococci are part of the commensal gut microbiota of mammals, with Enterococcus faecalis and Enterococcus faecium being the most clinically relevant species. This study assesses the prevalence and diversity of enterococcal species in cattle (n = 201) and pig (n = [...] Read more.

Enterococci are part of the commensal gut microbiota of mammals, with Enterococcus faecalis and Enterococcus faecium being the most clinically relevant species. This study assesses the prevalence and diversity of enterococcal species in cattle (n = 201) and pig (n = 249) cecal samples collected in 2017. Antimicrobial susceptibility profiles of E. faecium (n = 48) and E. faecalis (n = 84) were assessed by agar and microdilution methods. Resistance genes were screened through PCR and nine strains were analyzed by Whole Genome Sequencing. A wide range of enterococci species was found colonizing the intestines of pigs and cattle. Overall, the prevalence of resistance to critically important antibiotics was low (except for erythromycin), and no glycopeptide-resistant isolates were identified. Two daptomycin-resistant E. faecalis ST58 and ST93 were found. Linezolid-resistant strains of E. faecalis (n = 3) and E. faecium (n = 1) were detected. Moreover, oxazolidinone resistance determinants optrA (n = 8) and poxtA (n = 2) were found in E. faecalis (ST16, ST58, ST207, ST474, ST1178) and E. faecium (ST22, ST2138). Multiple variants of optrA were found in different genetic contexts, either in the chromosome or plasmids. We highlight the importance of animals as reservoirs of resistance genes to critically important antibiotics. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Antibiotic Alternatives in Livestock)

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12 pages, 1632 KiB

Open AccessEditor’s ChoiceArticle

Impact of COVID-19 on Antimicrobial Consumption and Spread of Multidrug-Resistance in Bacterial Infections

by Kibum Jeon, Seri Jeong, Nuri Lee, Min-Jeong Park, Wonkeun Song, Han-Sung Kim, Hyun Soo Kim and Jae-Seok Kim

Antibiotics 2022, 11(4), 535; https://doi.org/10.3390/antibiotics11040535 - 18 Apr 2022

Cited by 64 | Viewed by 5586

Abstract

The spread of COVID-19 pandemic may have affected antibiotic consumption patterns and the prevalence of colonized or infected by multidrug-resistant (MDR) bacteria. We investigated the differences in the consumption of antibiotics easily prone to resistance and the prevalence of MDR bacteria during the [...] Read more.

The spread of COVID-19 pandemic may have affected antibiotic consumption patterns and the prevalence of colonized or infected by multidrug-resistant (MDR) bacteria. We investigated the differences in the consumption of antibiotics easily prone to resistance and the prevalence of MDR bacteria during the COVID-19 pandemic (March 2020 to September 2021) compared to in the pre-pandemic period (March 2018 to September 2019). Data on usage of antibiotics and infections caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA) were obtained from hospitalized patients in four university hospitals. The consumption of penicillin with β-lactamase inhibitors (3.4% in ward, 5.8% in intensive care unit (ICU)), and carbapenems (25.9% in ward, 12.1% in ICU) increased during the pandemic period. The prevalence of MRSA (4.7%), VRE (49.0%), CRE (22.4%), and CRPA (20.1%) isolated in clinical samples from the ward and VRE (26.7%) and CRE (36.4%) isolated in clinical samples from the ICU were significantly increased, respectively. Meanwhile, only the prevalence of CRE (38.7%) isolated in surveillance samples from the ward increased. The COVID-19 pandemic is associated with increased consumption of antibiotics and has influenced the prevalence of infections caused by MDR isolates. Full article

(This article belongs to the Special Issue Social Dimensions of Antibiotic Resistance in Asia - a One Health Perspective)

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18 pages, 1224 KiB

Open AccessEditor’s ChoiceReview

Companion Animals—An Overlooked and Misdiagnosed Reservoir of Carbapenem Resistance

by Joana Moreira da Silva, Juliana Menezes, Cátia Marques and Constança Ferreira Pomba

Antibiotics 2022, 11(4), 533; https://doi.org/10.3390/antibiotics11040533 - 17 Apr 2022

Cited by 33 | Viewed by 5970

Abstract

The dissemination of antimicrobial-resistance is a major global threat affecting both human and animal health. Carbapenems are human use β-lactams of last resort; thus. the dissemination of carbapenemase-producing (CP) bacteria creates severe limitations for the treatment of multidrug-resistant bacteria in hospitalized patients. Even [...] Read more.

The dissemination of antimicrobial-resistance is a major global threat affecting both human and animal health. Carbapenems are human use β-lactams of last resort; thus. the dissemination of carbapenemase-producing (CP) bacteria creates severe limitations for the treatment of multidrug-resistant bacteria in hospitalized patients. Even though carbapenems are not routinely used in veterinary medicine, reports of infection or colonization by carbapenemase-producing Enterobacterales in companion animals are being reported. NDM-5 and OXA-48-like carbapenemases are among the most frequently reported in companion animals. Like in humans, Escherichia coli and Klebsiella pneumoniae are the most represented CP Enterobacterales found in companion animals, alongside with Acinetobacter baumannii. Considering that the detection of carbapenemase-producing Enterobacterales presents several difficulties, misdiagnosis of CP bacteria in companion animals may lead to important animal and public-health consequences. It is of the upmost importance to ensure an adequate monitoring and detection of CP bacteria in veterinary microbiology in order to safeguard animal health and minimise its dissemination to humans and the environment. This review encompasses an overview of the carbapenemase detection methods currently available, aiming to guide veterinary microbiologists on the best practices to improve its detection for clinical or research purposes. Full article

(This article belongs to the Special Issue Antibiotic Resistance and Antimicrobial Use in Companion Animals)

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25 pages, 3276 KiB

Open AccessEditor’s ChoiceReview

Diagnosis of Bloodstream Infections: An Evolution of Technologies towards Accurate and Rapid Identification and Antibiotic Susceptibility Testing

by Kristel C. Tjandra, Nikhil Ram-Mohan, Ryuichiro Abe, Marjan M. Hashemi, Jyong-Huei Lee, Siew Mei Chin, Manuel A. Roshardt, Joseph C. Liao, Pak Kin Wong and Samuel Yang

Antibiotics 2022, 11(4), 511; https://doi.org/10.3390/antibiotics11040511 - 12 Apr 2022

Cited by 33 | Viewed by 9584

Abstract

Bloodstream infections (BSI) are a leading cause of death worldwide. The lack of timely and reliable diagnostic practices is an ongoing issue for managing BSI. The current gold standard blood culture practice for pathogen identification and antibiotic susceptibility testing is time-consuming. Delayed diagnosis [...] Read more.

Bloodstream infections (BSI) are a leading cause of death worldwide. The lack of timely and reliable diagnostic practices is an ongoing issue for managing BSI. The current gold standard blood culture practice for pathogen identification and antibiotic susceptibility testing is time-consuming. Delayed diagnosis warrants the use of empirical antibiotics, which could lead to poor patient outcomes, and risks the development of antibiotic resistance. Hence, novel techniques that could offer accurate and timely diagnosis and susceptibility testing are urgently needed. This review focuses on BSI and highlights both the progress and shortcomings of its current diagnosis. We surveyed clinical workflows that employ recently approved technologies and showed that, while offering improved sensitivity and selectivity, these techniques are still unable to deliver a timely result. We then discuss a number of emerging technologies that have the potential to shorten the overall turnaround time of BSI diagnosis through direct testing from whole blood—while maintaining, if not improving—the current assay’s sensitivity and pathogen coverage. We concluded by providing our assessment of potential future directions for accelerating BSI pathogen identification and the antibiotic susceptibility test. While engineering solutions have enabled faster assay turnaround, further progress is still needed to supplant blood culture practice and guide appropriate antibiotic administration for BSI patients. Full article

(This article belongs to the Special Issue Rapid Diagnostics of the Antimicrobial Resistance)

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8 pages, 833 KiB

Open AccessEditor’s ChoiceOpinion

Persistent Bacterial Infections, Antibiotic Treatment Failure, and Microbial Adaptive Evolution

by Ruggero La Rosa, Helle Krogh Johansen and Søren Molin

Antibiotics 2022, 11(3), 419; https://doi.org/10.3390/antibiotics11030419 - 21 Mar 2022

Cited by 32 | Viewed by 6421

Abstract

Antibiotic resistance is expected by the WHO to be the biggest threat to human health before 2050. In this overview, we argue that this prediction may in fact be too optimistic because it is often overlooked that many bacterial infections frequently ‘go under [...] Read more.

Antibiotic resistance is expected by the WHO to be the biggest threat to human health before 2050. In this overview, we argue that this prediction may in fact be too optimistic because it is often overlooked that many bacterial infections frequently ‘go under the radar’ because they are difficult to diagnose and characterize. Due to our lifestyle, persistent infections caused by opportunistic bacteria—well-known or emerging—show increasing success of infecting patients with reduced defense capacity, and often antibiotics fail to be sufficiently effective, even if the bacteria are susceptible, leaving small bacterial populations unaffected by treatment in the patient. The mechanisms behind infection persistence are multiple, and therefore very difficult to diagnose in the laboratory and to treat. In contrast to antibiotic resistance associated with acute infections caused by traditional bacterial pathogens, genetic markers associated with many persistent infections are imprecise and mostly without diagnostic value. In the absence of effective eradication strategies, there is a significant risk that persistent infections may eventually become highly resistant to antibiotic treatment due to the accumulation of genomic mutations, which will transform colonization into persistence. Full article

(This article belongs to the Special Issue How Far Are We from Predicting the Evolution of Antibiotic Resistance?)

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14 pages, 671 KiB

Open AccessEditor’s ChoiceReview

Understanding microRNAs in the Context of Infection to Find New Treatments against Human Bacterial Pathogens

by Álvaro Mourenza, Blanca Lorente-Torres, Elena Durante, Jesús Llano-Verdeja, Jesús F. Aparicio, Arsenio Fernández-López, José A. Gil, Luis M. Mateos and Michal Letek

Antibiotics 2022, 11(3), 356; https://doi.org/10.3390/antibiotics11030356 - 8 Mar 2022

Cited by 17 | Viewed by 5196

Abstract

The development of RNA-based anti-infectives has gained interest with the successful application of mRNA-based vaccines. Small RNAs are molecules of RNA of <200 nucleotides in length that may control the expression of specific genes. Small RNAs include small interference RNAs (siRNAs), Piwi-interacting RNAs [...] Read more.

The development of RNA-based anti-infectives has gained interest with the successful application of mRNA-based vaccines. Small RNAs are molecules of RNA of <200 nucleotides in length that may control the expression of specific genes. Small RNAs include small interference RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), or microRNAs (miRNAs). Notably, the role of miRNAs on the post-transcriptional regulation of gene expression has been studied in detail in the context of cancer and many other genetic diseases. However, it is also becoming apparent that some human miRNAs possess important antimicrobial roles by silencing host genes essential for the progress of bacterial or viral infections. Therefore, their potential use as novel antimicrobial therapies has gained interest during the last decade. The challenges of the transport and delivery of miRNAs to target cells are important, but recent research with exosomes is overcoming the limitations in RNA-cellular uptake, avoiding their degradation. Therefore, in this review, we have summarised the latest developments in the exosomal delivery of miRNA-based therapies, which may soon be another complementary treatment to pathogen-targeted antibiotics that could help solve the problem caused by multidrug-resistant bacteria. Full article

(This article belongs to the Special Issue Alternative Approaches to Treating Antimicrobial Resistant Infections)

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12 pages, 515 KiB

Open AccessEditor’s ChoiceReview

Review and Comparison of Antimicrobial Resistance Gene Databases

by Márton Papp and Norbert Solymosi

Antibiotics 2022, 11(3), 339; https://doi.org/10.3390/antibiotics11030339 - 4 Mar 2022

Cited by 48 | Viewed by 12833

Abstract

As the prevalence of antimicrobial resistance genes is increasing in microbes, we are facing the return of the pre-antibiotic era. Consecutively, the number of studies concerning antibiotic resistance and its spread in the environment is rapidly growing. Next generation sequencing technologies are widespread [...] Read more.

As the prevalence of antimicrobial resistance genes is increasing in microbes, we are facing the return of the pre-antibiotic era. Consecutively, the number of studies concerning antibiotic resistance and its spread in the environment is rapidly growing. Next generation sequencing technologies are widespread used in many areas of biological research and antibiotic resistance is no exception. For the rapid annotation of whole genome sequencing and metagenomic results considering antibiotic resistance, several tools and data resources were developed. These databases, however, can differ fundamentally in the number and type of genes and resistance determinants they comprise. Furthermore, the annotation structure and metadata stored in these resources can also contribute to their differences. Several previous reviews were published on the tools and databases of resistance gene annotation; however, to our knowledge, no previous review focused solely and in depth on the differences in the databases. In this review, we compare the most well-known and widely used antibiotic resistance gene databases based on their structure and content. We believe that this knowledge is fundamental for selecting the most appropriate database for a research question and for the development of new tools and resources of resistance gene annotation. Full article

(This article belongs to the Special Issue Genetic Background of Antimicrobial Resistance)

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7 pages, 966 KiB

Open AccessEditor’s ChoiceCase Report

Possible COVID-19-Associated Pulmonary Aspergillosis Due to Aspergillus niger in Greece

by Maria Katsiari, Angeliki Mavroidi, Eleftheria Palla, Konstantina Zourla, Theodoros Alonistiotis, Kyriakos Ntorlis, Charikleia Nikolaou, Georgia Vrioni and Athanasios Tsakris

Antibiotics 2022, 11(3), 300; https://doi.org/10.3390/antibiotics11030300 - 23 Feb 2022

Cited by 4 | Viewed by 2714

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes direct damage to the pulmonary epithelium, enabling Aspergillus invasion. Rapid progression and high mortality of invasive aspergillosis have been reported. In the present study, we report a rare case of possible COVID-19-associated pulmonary aspergillosis (CAPA) [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes direct damage to the pulmonary epithelium, enabling Aspergillus invasion. Rapid progression and high mortality of invasive aspergillosis have been reported. In the present study, we report a rare case of possible COVID-19-associated pulmonary aspergillosis (CAPA) caused by A. niger in a Greek patient. Diagnosis was based on ECMM/ISHAM specific criteria and the new algorithm “BM-AspICU” for the invasive pulmonary aspergillosis diagnostic strategy. The fungal isolate was recovered in a non-bronchoalveolar lavage (non-BAL) sample and its identification was performed by standard macroscopic and microscopic morphological studies. MALDI-TOF analysis confirmed the identification of A. niger. In addition, galactomannan antigen and Aspergillus real-time PCR testing were positive in the non-BAL sample, while in serum they proved negative. The A. niger isolate showed an MIC for fluconazole ≥128 μg/mL, for itraconazole and posaconazole 0.25 μg/mL, for voriconazole 0.5 μg/mL, for flucytosine 4 μg/mL, for amphotericin B 1 μg/mL, and for all echinocandins (caspofungin, anidulafungin, micafungin) >8 μg/mL. The patient was initially treated with voriconazole; amphotericin B was subsequently added, when a significant progression of cavitation was demonstrated on chest computed tomography. A. niger was not isolated in subsequent samples and the patient’s unfavorable outcome was attributed to septic shock caused by a pandrug-resistant Acinetobacter baumannii strain. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Fungal Infections)

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16 pages, 1579 KiB

Open AccessEditor’s ChoiceArticle

Stapling of Peptides Potentiates the Antibiotic Treatment of Acinetobacter baumannii In Vivo

by Gina K. Schouten, Felix M. Paulussen, Oscar P. Kuipers, Wilbert Bitter, Tom N. Grossmann and Peter van Ulsen

Antibiotics 2022, 11(2), 273; https://doi.org/10.3390/antibiotics11020273 - 19 Feb 2022

Cited by 15 | Viewed by 4779

Abstract

The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to [...] Read more.

The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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14 pages, 2021 KiB

Open AccessEditor’s ChoiceSystematic Review

Safety and Efficacy of Devices Delivering Inhaled Antibiotics among Adults with Non-Cystic Fibrosis Bronchiectasis: A Systematic Review and a Network Meta-Analysis

by Sofia Tejada, Sergio Ramírez-Estrada, Carlos G. Forero, Miguel Gallego, Joan B. Soriano, Pablo A. Cardinal-Fernández, Stephan Ehrmann and Jordi Rello

Antibiotics 2022, 11(2), 275; https://doi.org/10.3390/antibiotics11020275 - 19 Feb 2022

Cited by 7 | Viewed by 4266

Abstract

It remains unknown whether the type of aerosol generating device is affecting efficacy and safety among non-cystic fibrosis bronchiectasis (NCFB) adults. The proposal of this network meta-analysis (NMA) is to evaluate effectiveness and safety of inhaled antibiotics administered via dry powder inhaler (DPI) [...] Read more.

It remains unknown whether the type of aerosol generating device is affecting efficacy and safety among non-cystic fibrosis bronchiectasis (NCFB) adults. The proposal of this network meta-analysis (NMA) is to evaluate effectiveness and safety of inhaled antibiotics administered via dry powder inhaler (DPI) and via nebulizers (SVN) among adult patients with NCFB. Inclusion criteria were randomized-controlled trials, adults (≥18 years) with NCFB, and inhaled antibiotics administered via DPI as intervention. Search strategy was performed in PubMed, Web of Science, and Cochrane Library from 2000 to 2019. Sixteen trials (2870 patients) were included. Three trials (all ciprofloxacin) used DPIs and thirteen used SVN (three ciprofloxacin). Both DPI and SVN devices achieved similar safety outcomes (adverse events, antibiotic discontinuation, severe adverse events, and bronchospasm). Administration of ciprofloxacin via DPI significantly improved time to first exacerbation (87 days, 95% CI 34.3–139.7) and quality of life (MD −7.52; 95% CI −13.06 to −1.98) when compared with via SVN. No other significant differences were documented in clinical efficacy (at least one exacerbation, FEV₁% predicted) and microbiologic response (bacterial eradication, emergence of new potential pathogens, and emergence of antimicrobial resistance) when comparing devices. Our NMA documented that time to first exacerbation and quality of life, were more favorable for DPIs. Decisions on the choice of devices should incorporate these findings plus other criteria, such as simplicity, costs or maintenance requirements. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Jordi Rello—Outstanding Contributions in the Fields of Management of Severe Infections and Sepsis)

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52 pages, 4389 KiB

Open AccessEditor’s ChoiceReview

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

by Javier Santos-Aberturas and Natalia M. Vior

Antibiotics 2022, 11(2), 195; https://doi.org/10.3390/antibiotics11020195 - 2 Feb 2022

Cited by 12 | Viewed by 6762

Abstract

Bacterial secondary metabolites represent an invaluable source of bioactive molecules for the pharmaceutical and agrochemical industries. Although screening campaigns for the discovery of new compounds have traditionally been strongly biased towards the study of soil-dwelling Actinobacteria, the current antibiotic resistance and discovery crisis [...] Read more.

Bacterial secondary metabolites represent an invaluable source of bioactive molecules for the pharmaceutical and agrochemical industries. Although screening campaigns for the discovery of new compounds have traditionally been strongly biased towards the study of soil-dwelling Actinobacteria, the current antibiotic resistance and discovery crisis has brought a considerable amount of attention to the study of previously neglected bacterial sources of secondary metabolites. The development and application of new screening, sequencing, genetic manipulation, cultivation and bioinformatic techniques have revealed several other groups of bacteria as producers of striking chemical novelty. Biosynthetic machineries evolved from independent taxonomic origins and under completely different ecological requirements and selective pressures are responsible for these structural innovations. In this review, we summarize the most important discoveries related to secondary metabolites from alternative bacterial sources, trying to provide the reader with a broad perspective on how technical novelties have facilitated the access to the bacterial metabolic dark matter. Full article

(This article belongs to the Special Issue Challenges and Opportunities in Antibiotic Biosynthesis and Development)

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15 pages, 1624 KiB

Open AccessEditor’s ChoiceReview

Air Ambulance: Antimicrobial Power of Bacterial Volatiles

by Alexander Lammers, Michael Lalk and Paolina Garbeva

Antibiotics 2022, 11(1), 109; https://doi.org/10.3390/antibiotics11010109 - 14 Jan 2022

Cited by 18 | Viewed by 4319

Abstract

We are currently facing an antimicrobial resistance crisis, which means that a lot of bacterial pathogens have developed resistance to common antibiotics. Hence, novel and innovative solutions are urgently needed to combat resistant human pathogens. A new source of antimicrobial compounds could be [...] Read more.

We are currently facing an antimicrobial resistance crisis, which means that a lot of bacterial pathogens have developed resistance to common antibiotics. Hence, novel and innovative solutions are urgently needed to combat resistant human pathogens. A new source of antimicrobial compounds could be bacterial volatiles. Volatiles are ubiquitous produced, chemically divers and playing essential roles in intra- and interspecies interactions like communication and antimicrobial defense. In the last years, an increasing number of studies showed bioactivities of bacterial volatiles, including antibacterial, antifungal and anti-oomycete activities, indicating bacterial volatiles as an exciting source for novel antimicrobial compounds. In this review we introduce the chemical diversity of bacterial volatiles, their antimicrobial activities and methods for testing this activity. Concluding, we discuss the possibility of using antimicrobial volatiles to antagonize the antimicrobial resistance crisis. Full article

(This article belongs to the Special Issue The Ecological Role of Antibiotic Production in Bacteria)

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11 pages, 481 KiB

Open AccessEditor’s ChoiceArticle

Factors Affecting Antibiotic Prescription among Hospital Physicians in a Low-Antimicrobial-Resistance Country: A Qualitative Study

by Ingrid Christensen, Jon Birger Haug, Dag Berild, Jørgen Vildershøj Bjørnholt, Brita Skodvin and Lars-Petter Jelsness-Jørgensen

Antibiotics 2022, 11(1), 98; https://doi.org/10.3390/antibiotics11010098 - 13 Jan 2022

Cited by 18 | Viewed by 4978

Abstract

Antimicrobial resistance (AMR) is a threat to hospital patients. Antimicrobial stewardship programs (ASPs) can counteract AMR. To optimize ASPs, we need to understand what affects physicians’ antibiotic prescription from several contexts. In this study, we aimed to explore the factors affecting hospital physicians’ [...] Read more.

Antimicrobial resistance (AMR) is a threat to hospital patients. Antimicrobial stewardship programs (ASPs) can counteract AMR. To optimize ASPs, we need to understand what affects physicians’ antibiotic prescription from several contexts. In this study, we aimed to explore the factors affecting hospital physicians’ antibiotic choices in a low-resistance country to identify potential targets for future ASPs. We interviewed 14 physicians involved in antibiotic prescription in a Norwegian hospital. The interviews were audiotaped, transcribed verbatim, and analyzed using thematic analysis. The main factors affecting antibiotic prescription were a high work pressure, insufficient staff resources, and uncertainties regarding clinical decisions. Treatment expectations from patients and next of kin, benevolence towards the patients, suboptimal microbiological testing, and limited time for infectious disease specialists to offer advisory services also affected the antibiotic choices. Future ASP efforts should evaluate the system organization and prioritizations to address and manage potential time-pressure issues. To limit the use of broad-spectrum antibiotics, improving microbiology testing and the routines for consultations with infectious disease specialists seems beneficial. We also identified a need among the prescribing physicians for a debate on ethical antibiotic questions. Full article

(This article belongs to the Special Issue Antimicrobial Prescribing and Stewardship, 2nd Volume)

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24 pages, 2260 KiB

Open AccessEditor’s ChoiceReview

Biofilms in Surgical Site Infections: Recent Advances and Novel Prevention and Eradication Strategies

by Andriy Hrynyshyn, Manuel Simões and Anabela Borges

Antibiotics 2022, 11(1), 69; https://doi.org/10.3390/antibiotics11010069 - 7 Jan 2022

Cited by 67 | Viewed by 9118

Abstract

Surgical site infections (SSIs) are common postoperative occurrences due to contamination of the surgical wound or implanted medical devices with community or hospital-acquired microorganisms, as well as other endogenous opportunistic microbes. Despite numerous rules and guidelines applied to prevent these infections, SSI rates [...] Read more.

Surgical site infections (SSIs) are common postoperative occurrences due to contamination of the surgical wound or implanted medical devices with community or hospital-acquired microorganisms, as well as other endogenous opportunistic microbes. Despite numerous rules and guidelines applied to prevent these infections, SSI rates are considerably high, constituting a threat to the healthcare system in terms of morbidity, prolonged hospitalization, and death. Approximately 80% of human SSIs, including chronic wound infections, are related to biofilm-forming bacteria. Biofilm-associated SSIs are extremely difficult to treat with conventional antibiotics due to several tolerance mechanisms provided by the multidrug-resistant bacteria, usually arranged as polymicrobial communities. In this review, novel strategies to control, i.e., prevent and eradicate, biofilms in SSIs are presented and discussed, focusing mainly on two attractive approaches: the use of nanotechnology-based composites and natural plant-based products. An overview of new therapeutic agents and strategic approaches to control epidemic multidrug-resistant pathogenic microorganisms, particularly when biofilms are present, is provided alongside other combinatorial approaches as attempts to obtain synergistic effects with conventional antibiotics and restore their efficacy to treat biofilm-mediated SSIs. Some detection and real-time monitoring systems to improve biofilm control strategies and diagnosis of human infections are also discussed. Full article

(This article belongs to the Special Issue Nature Inspired Antibiotic Adjuvants to Face the Problem of Multidrug Resistance and Biofilm Infections)

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26 pages, 11164 KiB

Open AccessEditor’s ChoiceArticle

Antimicrobial Resistance and Environmental Health: A Water Stewardship Framework for Global and National Action

by Rachel A. Kaiser, Lina Taing and Himesh Bhatia

Antibiotics 2022, 11(1), 63; https://doi.org/10.3390/antibiotics11010063 - 5 Jan 2022

Cited by 20 | Viewed by 6147

Abstract

Antimicrobial resistance (AMR) is a global health crisis that affects all life on Earth. In 2015, the World Health Organization developed guidance to combat AMR in accordance with a One Health framework considering human, animal, and environment sectors of planetary health. This study [...] Read more.

Antimicrobial resistance (AMR) is a global health crisis that affects all life on Earth. In 2015, the World Health Organization developed guidance to combat AMR in accordance with a One Health framework considering human, animal, and environment sectors of planetary health. This study reviewed global guidance and 25 National Action Plans to evaluate thematic priorities in One Health AMR approaches using a novel framework that additionally facilitated the identification of water-related stewardship gaps, as water resources are recognized as the primary environmental AMR reservoir and dissemination pathway. This review found that global and national stewardship primarily focuses on mitigating antibiotic use in the human and animal sectors, overlooking environmental drivers, particularly diverse environmental waters. The findings of this study highlight the need to broaden the scope of water-related AMR concerns beyond water, sanitation, and hygiene (WASH) infrastructure for water supply and wastewater treatment, and account for environmental waters in AMR development and dissemination, particularly in low-income countries where half a billion people rely on environmental waters to meet daily needs. Equitably accounting for water environments, supplies, and waste in AMR prevention, mitigation, surveillance, and innovation can significantly enhance the integration of environmental objectives in One Health AMR stewardship. Full article

(This article belongs to the Special Issue Policy Design, Implementation and Governance of Antimicrobial Resistance)

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32 pages, 15897 KiB

Open AccessEditor’s ChoiceReview

Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

by Abolfazl Dashtbani-Roozbehani and Melissa H. Brown

Antibiotics 2021, 10(12), 1502; https://doi.org/10.3390/antibiotics10121502 - 7 Dec 2021

Cited by 60 | Viewed by 8884

Abstract

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with [...] Read more.

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use. Full article

(This article belongs to the Special Issue Antibacterial, Antibiofilm and Anti-virulence Activity Research of Both Natural and Synthetic Products)

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12 pages, 2200 KiB

Open AccessEditor’s ChoiceArticle

Characterization and Molecular Determinants for β-Lactam Specificity of the Multidrug Efflux Pump AcrD from Salmonella typhimurium

by Jenifer Cuesta Bernal, Jasmin El-Delik, Stephan Göttig and Klaas M. Pos

Antibiotics 2021, 10(12), 1494; https://doi.org/10.3390/antibiotics10121494 - 6 Dec 2021

Cited by 5 | Viewed by 3358

Abstract

Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate [...] Read more.

Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate specificity. Similarly to many other RND efflux pump systems, AcrAD-TolC confers resistance toward SDS, novobiocin and deoxycholate. In contrast to the other pumps, however, it in addition confers resistance against aminoglycosides and dianionic β-lactams, such as sulbenicillin, aztreonam and carbenicillin. Here, we could show that AcrD from Salmonella typhimurium confers resistance toward several hitherto unreported AcrD substrates such as temocillin, dicloxacillin, cefazolin and fusidic acid. In order to address the molecular determinants of the S. typhimurium AcrD substrate specificity, we conducted substitution analyses in the putative access and deep binding pockets and in the TM1/TM2 groove region. The variants were tested in E. coli ΔacrBΔacrD against β-lactams oxacillin, carbenicillin, aztreonam and temocillin. Deep binding pocket variants N136A, D276A and Y327A; access pocket variant R625A; and variants with substitutions in the groove region between TM1 and TM2 conferred a sensitive phenotype and might, therefore, be involved in anionic β-lactam export. In contrast, lower susceptibilities were observed for E. coli cells harbouring deep binding pocket variants T139A, D176A, S180A, F609A, T611A and F627A and the TM1/TM2 groove variant I337A. This study provides the first insights of side chains involved in drug binding and transport for AcrD from S. typhimurium. Full article

(This article belongs to the Special Issue The Structural and Functional Study of Efflux Pumps Belonging to the RND Transporters Family from Gram-Negative Bacteria)

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36 pages, 3978 KiB

Open AccessEditor’s ChoiceReview

Treating Bacterial Infections with Bacteriophage-Based Enzybiotics: In Vitro, In Vivo and Clinical Application

by Katarzyna M. Danis-Wlodarczyk, Daniel J. Wozniak and Stephen T. Abedon

Antibiotics 2021, 10(12), 1497; https://doi.org/10.3390/antibiotics10121497 - 6 Dec 2021

Cited by 86 | Viewed by 14128

Abstract

Over the past few decades, we have witnessed a surge around the world in the emergence of antibiotic-resistant bacteria. This global health threat arose mainly due to the overuse and misuse of antibiotics as well as a relative lack of new drug classes [...] Read more.

Over the past few decades, we have witnessed a surge around the world in the emergence of antibiotic-resistant bacteria. This global health threat arose mainly due to the overuse and misuse of antibiotics as well as a relative lack of new drug classes in development pipelines. Innovative antibacterial therapeutics and strategies are, therefore, in grave need. For the last twenty years, antimicrobial enzymes encoded by bacteriophages, viruses that can lyse and kill bacteria, have gained tremendous interest. There are two classes of these phage-derived enzymes, referred to also as enzybiotics: peptidoglycan hydrolases (lysins), which degrade the bacterial peptidoglycan layer, and polysaccharide depolymerases, which target extracellular or surface polysaccharides, i.e., bacterial capsules, slime layers, biofilm matrix, or lipopolysaccharides. Their features include distinctive modes of action, high efficiency, pathogen specificity, diversity in structure and activity, low possibility of bacterial resistance development, and no observed cross-resistance with currently used antibiotics. Additionally, and unlike antibiotics, enzybiotics can target metabolically inactive persister cells. These phage-derived enzymes have been tested in various animal models to combat both Gram-positive and Gram-negative bacteria, and in recent years peptidoglycan hydrolases have entered clinical trials. Here, we review the testing and clinical use of these enzymes. Full article

(This article belongs to the Special Issue Bacteriolysins and Other Phage-Based Strategies to Combat Bacterial Infections)

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19 pages, 552 KiB

Open AccessEditor’s ChoiceReview

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

by Wisse van Os and Markus Zeitlinger

Antibiotics 2021, 10(12), 1485; https://doi.org/10.3390/antibiotics10121485 - 4 Dec 2021

Cited by 14 | Viewed by 4950

Abstract

Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from [...] Read more.

Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection. Full article

(This article belongs to the Special Issue 10th Anniversary of Antibiotics—Recent Advances in Pharmacodynamics of Antibiotics)

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15 pages, 3305 KiB

Open AccessEditor’s ChoiceArticle

Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials

by Susanne Paukner, David Mariano, Anita F. Das, Gregory J. Moran, Christian Sandrock, Ken B. Waites and Thomas M. File, Jr.

Antibiotics 2021, 10(12), 1489; https://doi.org/10.3390/antibiotics10121489 - 4 Dec 2021

Cited by 9 | Viewed by 4357

Abstract

Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with [...] Read more.

Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with community-acquired bacterial pneumonia caused by atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae). In LEAP-1, participants received intravenous lefamulin 150 mg every 12 h for 5–7 days or moxifloxacin 400 mg every 24 h for 7 days, with optional intravenous-to-oral switch. In LEAP-2, participants received oral lefamulin 600 mg every 12 h for 5 days or moxifloxacin 400 mg every 24 h for 7 days. Primary outcomes were early clinical response at 96 ± 24 h after first dose and investigator assessment of clinical response at test of cure (5–10 days after last dose). Atypical pathogens were identified in 25.0% (91/364) of lefamulin-treated patients and 25.2% (87/345) of moxifloxacin-treated patients; most were identified by ≥1 standard diagnostic modality (M. pneumoniae 71.2% [52/73]; L. pneumophila 96.9% [63/65]; C. pneumoniae 79.3% [46/58]); the most common standard diagnostic modality was serology. In terms of disease severity, more than 90% of patients had CURB-65 (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, blood pressure <90 mm Hg systolic or ≤60 mm Hg diastolic, and age ≥ 65 years) scores of 0–2; approximately 50% of patients had PORT (Pneumonia Outcomes Research Team) risk class of III, and the remaining patients were more likely to have PORT risk class of II or IV versus V. In patients with atypical pathogens, early clinical response (lefamulin 84.4–96.6%; moxifloxacin 90.3–96.8%) and investigator assessment of clinical response at test of cure (lefamulin 74.1–89.7%; moxifloxacin 74.2–97.1%) were high and similar between arms. Treatment-emergent adverse event rates were similar in the lefamulin (34.1% [31/91]) and moxifloxacin (32.2% [28/87]) groups. Limitations to this analysis include its post hoc nature, the small numbers of patients infected with atypical pathogens, the possibility of PCR-based diagnostic methods to identify non-etiologically relevant pathogens, and the possibility that these findings may not be generalizable to all patients. Lefamulin as short-course empiric monotherapy, including 5-day oral therapy, was well tolerated in adults with community-acquired bacterial pneumonia and demonstrated high clinical response rates against atypical pathogens. Full article

(This article belongs to the Special Issue One Health in Mycoplasmas: Antimicrobial Susceptibility and Resistance in Mycoplasmas Infecting Humans, Animals, Plants and Insects)

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18 pages, 1788 KiB

Open AccessEditor’s ChoiceArticle

Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes

by Sandrine Verstraeten, Lucy Catteau, Laila Boukricha, Joelle Quetin-Leclercq and Marie-Paule Mingeot-Leclercq

Antibiotics 2021, 10(11), 1381; https://doi.org/10.3390/antibiotics10111381 - 11 Nov 2021

Cited by 18 | Viewed by 3378

Abstract

Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential [...] Read more.

Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential synergy between ampicillin and plant-derived antibiotics (pentacyclic triterpenes, ursolic acid (UA) and oleanolic acid (OA)) towards MRSA (ATCC33591 and COL) and the mechanisms involved. We calculated the Fractional Inhibitory Concentration Index (FICI) and demonstrated synergy. We monitored fluorescence of Bodipy-TR-Cadaverin, propidium iodide and membrane potential-sensitive probe for determining the ability of UA and OA to bind to lipoteichoic acids (LTA), and to induce membrane permeabilization and depolarization, respectively. Both pentacyclic triterpenes were able to bind to LTA and to induce membrane permeabilization and depolarization in a dose-dependent fashion. These effects were not accompanied by significant changes in cellular concentration of pentacyclic triterpenes and/or ampicillin, suggesting an effect mediated through lipid membranes. We therefore focused on membranous effects induced by UA and OA, and we investigated on models of membranes, the role of specific lipids including phosphatidylglycerol and cardiolipin. The effect induced on membrane fluidity, permeability and ability to fuse were studied by determining changes in fluorescence anisotropy of DPH/generalized polarization of Laurdan, calcein release from liposomes, fluorescence dequenching of octadecyl-rhodamine B and liposome-size, respectively. Both UA and OA showed a dose-dependent effect with membrane rigidification, increase of membrane permeabilization and fusion. Except for the effect on membrane fluidity, the effect of UA was consistently higher compared with that obtained with OA, suggesting the role of methyl group position. All together the data demonstrated the potential role of compounds acting on lipid membranes for enhancing the activity of other antibiotics, like ampicillin and inducing synergy. Such combinations offer an opportunity to explore a larger antibiotic chemical space. Full article

(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)

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11 pages, 648 KiB

Open AccessEditor’s ChoiceArticle

Correlation between Previous Antibiotic Exposure and COVID-19 Severity. A Population-Based Cohort Study

by Carl Llor, Dan Ouchi, Maria Giner-Soriano, Ana García-Sangenís, Lars Bjerrum and Rosa Morros

Antibiotics 2021, 10(11), 1364; https://doi.org/10.3390/antibiotics10111364 - 8 Nov 2021

Cited by 17 | Viewed by 6537

Abstract

We examined the correlation between previous antibiotic exposure and COVID-19 severity using a population-based observational matched cohort study with patient level data obtained for more than 5.8 million people registered in SIDIAP in Catalonia, Spain. We included all patients newly diagnosed with COVID-19 [...] Read more.

We examined the correlation between previous antibiotic exposure and COVID-19 severity using a population-based observational matched cohort study with patient level data obtained for more than 5.8 million people registered in SIDIAP in Catalonia, Spain. We included all patients newly diagnosed with COVID-19 from March to June 2020 and identified all their antibiotic prescriptions in the previous two years. We used a composite severity endpoint, including pneumonia, hospital admission and death due to COVID-19. We examined the influence of high antibiotic exposure (>4 regimens), exposure to highest priority critically important antimicrobials (HPCIA) and recent exposure. Potential confounders were adjusted by logistic regression. A total of 280,679 patients were diagnosed with COVID-19, 146,656 of whom were exposed to at least one antibiotic course (52.3%) during the preceding two years. A total of 25,222 presented severe COVID-19 infection (9%), and the risk of severity was highest among those exposed to antibiotics (OR 1.12; 95% CI: 1.04–1.21). Among all individuals exposed to antibiotics, high, recent and exposure to HPCIAs were correlated with increased COVID severity (OR 1.19; 95% CI: 1.14–1.26; 1.41; 95% CI: 1.36–1.46; and 1.35; 95% CI: 1.30–1.40, respectively). Our findings confirm a significant correlation between previous antibiotic exposure and increased severity of COVID-19 disease. Full article

(This article belongs to the Special Issue Antibiotics Use in Primary Care during COVID-19)

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19 pages, 3645 KiB

Open AccessEditor’s ChoiceArticle

Natural Bred ε²-Phages Have an Improved Host Range and Virulence against Uropathogenic Escherichia coli over Their Ancestor Phages

by Maria Loose, David Sáez Moreno, Michele Mutti, Eva Hitzenhammer, Zehra Visram, David Dippel, Susanne Schertler, Lenka Podpera Tišáková, Johannes Wittmann, Lorenzo Corsini and Florian Wagenlehner

Antibiotics 2021, 10(11), 1337; https://doi.org/10.3390/antibiotics10111337 - 1 Nov 2021

Cited by 13 | Viewed by 3792

Abstract

Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting [...] Read more.

Alternative treatments for Escherichia coli infections are urgently needed, and phage therapy is a promising option where antibiotics fail, especially for urinary tract infections (UTI). We used wastewater-isolated phages to test their lytic activity against a panel of 47 E. coli strains reflecting the diversity of strains found in UTI, including sequence type 131, 73 and 69. The plaquing host range (PHR) was between 13 and 63%. In contrast, the kinetic host range (KHR), describing the percentage of strains for which growth in suspension was suppressed for 24 h, was between 0% and 19%, substantially lower than the PHR. To improve the phage host range and their efficacy, we bred the phages by mixing and propagating cocktails on a subset of E. coli strains. The bred phages, which we termed evolution-squared ε²-phages, of a mixture of Myoviridae have KHRs up to 23% broader compared to their ancestors. Furthermore, using constant phage concentrations, Myoviridae ε²-phages suppressed the growth of higher bacterial inocula than their ancestors did. Thus, the ε²-phages were more virulent compared to their ancestors. Analysis of the genetic sequences of the ε²-phages with the broadest host range reveals that they are mosaic intercrossings of 2–3 ancestor phages. The recombination sites are distributed over the whole length of the genome. All ε²-phages are devoid of genes conferring lysogeny, antibiotic resistance, or virulence. Overall, this study shows that ε²-phages are remarkably more suitable than the wild-type phages for phage therapy. Full article

(This article belongs to the Special Issue Benefits of Bacteriophages to Combat Antibiotic-Resistant Bacteria)

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14 pages, 329 KiB

Open AccessEditor’s ChoiceSystematic Review

Antimicrobial Treatment Strategies for Stenotrophomonas maltophilia: A Focus on Novel Therapies

by Jean Gibb and Darren W. Wong

Antibiotics 2021, 10(10), 1226; https://doi.org/10.3390/antibiotics10101226 - 9 Oct 2021

Cited by 47 | Viewed by 12668

Abstract

Stenotrophomonas maltophilia is an urgent global threat due to its increasing incidence and intrinsic antibiotic resistance. Antibiotic development has focused on carbapenem-resistant Enterobacteriaceae, Pseudomonas, and Acinetobacter, with approved antibiotics in recent years having limited activity for Stenotrophomonas. Accordingly, novel treatment strategies for Stenotrophomonas [...] Read more.

Stenotrophomonas maltophilia is an urgent global threat due to its increasing incidence and intrinsic antibiotic resistance. Antibiotic development has focused on carbapenem-resistant Enterobacteriaceae, Pseudomonas, and Acinetobacter, with approved antibiotics in recent years having limited activity for Stenotrophomonas. Accordingly, novel treatment strategies for Stenotrophomonas are desperately needed. We conducted a systemic literature review and offer recommendations based on current evidence for a treatment strategy of Stenotrophomonas infection. Full article

(This article belongs to the Special Issue Epidemiology, Prognosis and Antimicrobial Treatment of Extensively Antibiotic-Resistant Bacterial Infections)

23 pages, 1563 KiB

Open AccessEditor’s ChoiceReview

Enterococcus spp. as a Producer and Target of Bacteriocins: A Double-Edged Sword in the Antimicrobial Resistance Crisis Context

by Ana C. Almeida-Santos, Carla Novais, Luísa Peixe and Ana R. Freitas

Antibiotics 2021, 10(10), 1215; https://doi.org/10.3390/antibiotics10101215 - 7 Oct 2021

Cited by 50 | Viewed by 7553

Abstract

Enterococcus spp. are one of the most frequent producers of bacteriocins (enterocins), which provides them with an advantage to compete in their natural environment, which is the gut of humans and many animals. The enterocins’ activity against microorganisms from different phylogenetic groups has [...] Read more.

Enterococcus spp. are one of the most frequent producers of bacteriocins (enterocins), which provides them with an advantage to compete in their natural environment, which is the gut of humans and many animals. The enterocins’ activity against microorganisms from different phylogenetic groups has raised interest in Enterococcus spp. in different contexts throughout the last decades, especially in the food industry. Nevertheless, some species can also cause opportunistic life-threatening infections and are frequently multidrug-resistant (MDR). Vancomycin-resistant Enterococcus (VRE), in particular, are an ongoing global challenge given the lack of therapeutic options. In this scenario, bacteriocins can offer a potential solution to this persistent threat, either alone or in combination with other antimicrobials. There are a handful of studies that demonstrate the advantages and applications of bacteriocins, especially against VRE. The purpose of this review is to present a current standpoint about the dual role of Enterococcus spp., from important producers to targets needed to be controlled, and the crucial role that enterocins may have in the expansion of enterococcal populations. Classification and distribution of enterocins, the current knowledge about the bacteriocinome of clinical enterococci, and the challenges of bacteriocin use in the fight against VRE infections are particularly detailed. Full article

(This article belongs to the Special Issue Alternatives to Antibiotics: Bacteriocins and Antimicrobial Peptides)

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20 pages, 696 KiB

Open AccessEditor’s ChoiceReview

Antibiotic Resistance: From Pig to Meat

by Xavier C. Monger, Alex-An Gilbert, Linda Saucier and Antony T. Vincent

Antibiotics 2021, 10(10), 1209; https://doi.org/10.3390/antibiotics10101209 - 5 Oct 2021

Cited by 74 | Viewed by 9572

Abstract

Pork meat is in high demand worldwide and this is expected to increase. Pork is often raised in intensive conditions, which is conducive to the spread of infectious diseases. Vaccines, antibiotics, and other biosafety measures help mitigate the impact of infectious diseases. However, [...] Read more.

Pork meat is in high demand worldwide and this is expected to increase. Pork is often raised in intensive conditions, which is conducive to the spread of infectious diseases. Vaccines, antibiotics, and other biosafety measures help mitigate the impact of infectious diseases. However, bacterial strains resistant to antibiotics are more and more frequently found in pig farms, animals, and the environment. It is now recognized that a holistic perspective is needed to sustainably fight antibiotic resistance, and that an integrated One Health approach is essential. With this in mind, this review tackles antibiotic resistance throughout the pork raising process, including their microbiome; many factors of their environment (agricultural workers, farms, rivers, etc.); and an overview of the impact of antibiotic resistance on pork meat, which is the end product available to consumers. Antibiotic resistance, while a natural process, is a public health concern. If we react, and act, collectively, it is expected to be, at least partially, reversible with judicious antibiotic usage and the development of innovative strategies and tools to foster animal health. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Terrestrial and Aquatic Farmed Animals: An Urgent One Health Issue for Sustainability)

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11 pages, 1836 KiB

Open AccessEditor’s ChoiceArticle

Nifedipine Potentiates Susceptibility of Salmonella Typhimurium to Different Classes of Antibiotics

by David Haschka, Manuel Grander, Johannes Eibensteiner, Stefanie Dichtl, Sabine Koppelstätter and Günter Weiss

Antibiotics 2021, 10(10), 1200; https://doi.org/10.3390/antibiotics10101200 - 1 Oct 2021

Cited by 3 | Viewed by 2617

Abstract

The calcium channel blocker nifedipine induces cellular iron export, thereby limiting the availability of the essential nutrient iron for intracellular pathogens, resulting in bacteriostatic activity. To study if nifedipine may exert a synergistic anti-microbial activity when combined with antibiotics, we used the mouse [...] Read more.

The calcium channel blocker nifedipine induces cellular iron export, thereby limiting the availability of the essential nutrient iron for intracellular pathogens, resulting in bacteriostatic activity. To study if nifedipine may exert a synergistic anti-microbial activity when combined with antibiotics, we used the mouse macrophage cell line RAW267.4, infected with the intracellular bacterium Salmonella Typhimurium, and exposed the cells to varying concentrations of nifedipine and/or ampicillin, azithromycin and ceftriaxone. We observed a significant additive effect of nifedipine in combination with various antibiotics, which was not observed when using Salmonella, with defects in iron uptake. Of interest, increasing intracellular iron levels increased the bacterial resistance to treatment with antibiotics or nifedipine or their combination. We further showed that nifedipine increases the expression of the siderophore-binding peptide lipocalin-2 and promotes iron storage within ferritin, where the metal is less accessible for bacteria. Our data provide evidence for an additive effect of nifedipine with conventional antibiotics against Salmonella, which is partly linked to reduced bacterial access to iron. Full article

(This article belongs to the Special Issue Development of Antimicrobial Biomaterials and Natural Alternatives against Biofilms and Implant-Related Infections)

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10 pages, 518 KiB

Open AccessEditor’s ChoiceArticle

Management of Common Infections in German Primary Care: A Cross-Sectional Survey of Knowledge and Confidence among General Practitioners and Outpatient Pediatricians

by Peter Konstantin Kurotschka, Elena Tiedemann, Dominik Wolf, Nicola Thier, Johannes Forster, Johannes G. Liese and Ildiko Gagyor

Antibiotics 2021, 10(9), 1131; https://doi.org/10.3390/antibiotics10091131 - 20 Sep 2021

Cited by 5 | Viewed by 3213

Abstract

Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners’ (GPs) and outpatient pediatricians’ [...] Read more.

Outpatient antibiotic use is closely related to antimicrobial resistance and in Germany, almost 70% of antibiotic prescriptions in human health are issued by primary care physicians (PCPs). The aim of this study was to explore PCPs, namely General Practitioners’ (GPs) and outpatient pediatricians’ (PDs) knowledge of guideline recommendations on rational antimicrobial treatment, the determinants of confidence in treatment decisions and the perceived need for training in this topic in a large sample of PCPs from southern Germany. Out of 3753 reachable PCPs, 1311 completed the survey (overall response rate = 34.9%). Knowledge of guideline recommendations and perceived confidence in making treatment decisions were high in both GPs and PDs. The two highest rated influencing factors on prescribing decisions were reported to be guideline recommendations and own clinical experiences, hence patients’ demands and expectations were judged as not influencing treatment decisions. The majority of physicians declared to have attended at least one specific training course on antibiotic use, yet almost all the participating PCPs declared to need more training on this topic. More studies are needed to explore how consultation-related and context-specific factors could influence antibiotic prescriptions in general and pediatric primary care in Germany beyond knowledge. Moreover, efforts should be undertaken to explore the training needs of PCPs in Germany, as this would serve the development of evidence-based educational interventions targeted to the improvement of antibiotic prescribing decisions rather than being focused solely on knowledge of guidelines. Full article

(This article belongs to the Special Issue Antibiotics and Infectious Respiratory Diseases)

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14 pages, 305 KiB

Open AccessEditor’s ChoiceArticle

A Study in a Regional Hospital of a Mid-Sized Spanish City Indicates a Major Increase in Infection/Colonization by Carbapenem-Resistant Bacteria, Coinciding with the COVID-19 Pandemic

by Estefanía Cano-Martín, Inés Portillo-Calderón, Patricia Pérez-Palacios, José María Navarro-Marí, María Amelia Fernández-Sierra and José Gutiérrez-Fernández

Antibiotics 2021, 10(9), 1127; https://doi.org/10.3390/antibiotics10091127 - 18 Sep 2021

Cited by 12 | Viewed by 3789

Abstract

Bacterial resistance to antibiotics has proven difficult to control over the past few decades. The large group of multidrug-resistant bacteria includes carbapenemase-producing bacteria (CPB), for which limited therapeutic options and infection control measures are available. Furthermore, carbapenemases associate with high-risk clones that are [...] Read more.

Bacterial resistance to antibiotics has proven difficult to control over the past few decades. The large group of multidrug-resistant bacteria includes carbapenemase-producing bacteria (CPB), for which limited therapeutic options and infection control measures are available. Furthermore, carbapenemases associate with high-risk clones that are defined by the sequence type (ST) to which each bacterium belongs. The objectives of this cross-sectional and retrospective study were to describe the CPB population isolated in a third-level hospital in Southern Spain between 2015 and 2020 and to establish the relationship between the ST and the epidemiological situation defined by the hospital. CPB were microbiologically studied in all rectal and pharyngeal swabs and clinical samples received between January 2015 and December 2020, characterizing isolates using MicroScan and mass spectrometry. Carbapenemases were detected by PCR and Sanger sequencing, and STs were assigned by multilocus sequence typing (MLST). Isolates were genetically related by pulsed-field gel electrophoresis using Xbal, Spel, or Apal enzymes. The episodes in which each CPB was isolated were recorded and classified as involved or non-involved in an outbreak. There were 320 episodes with CPB during the study period: 18 with K. pneumoniae, 14 with Klebisella oxytoca, 9 with Citrobacter freundii, 11 with Escherichia coli, 46 with Enterobacter cloacae, 70 with Acinetobacter baumannii, and 52 with Pseudomonas aeruginosa. The carbapenemase groups detected were OXA, VIM, KPC, and NDM with various subgroups. Synchronous relationships were notified between episodes of K. pneumoniae and outbreaks for ST15, ST258, ST307, and ST45, but not for the other CPB. There was a major increase in infections with CPB over the years, most notably during 2020, coinciding with the COVID-19 pandemic. This study highlights the usefulness of gene sequencing techniques to control the spread of these microorganisms, especially in healthcare centers. These techniques offer faster results, and a reduction in their cost may make their real-time application more feasible. The combination of epidemiological data with real-time molecular sequencing techniques can provide a major advance in the transmission control of these CPB and in the management of infected patients. Real-time sequencing is essential to increase precision and thereby control outbreaks and target infection prevention measures in a more effective manner. Full article

(This article belongs to the Special Issue Carbapenemase-Producing Enterobacterales)

13 pages, 1194 KiB

Open AccessEditor’s ChoiceArticle

Environmental and Pathogenic Carbapenem Resistant Bacteria Isolated from a Wastewater Treatment Plant Harbour Distinct Antibiotic Resistance Mechanisms

by Micaela Oliveira, Inês Carvalho Leonardo, Mónica Nunes, Ana Filipa Silva and Maria Teresa Barreto Crespo

Antibiotics 2021, 10(9), 1118; https://doi.org/10.3390/antibiotics10091118 - 16 Sep 2021

Cited by 18 | Viewed by 4303

Abstract

Wastewater treatment plants are important reservoirs and sources for the dissemination of antibiotic resistance into the environment. Here, two different groups of carbapenem resistant bacteria—the potentially environmental and the potentially pathogenic—were isolated from both the wastewater influent and discharged effluent of a full-scale [...] Read more.

Wastewater treatment plants are important reservoirs and sources for the dissemination of antibiotic resistance into the environment. Here, two different groups of carbapenem resistant bacteria—the potentially environmental and the potentially pathogenic—were isolated from both the wastewater influent and discharged effluent of a full-scale wastewater treatment plant and characterized by whole genome sequencing and antibiotic susceptibility testing. Among the potentially environmental isolates, there was no detection of any acquired antibiotic resistance genes, which supports the idea that their resistance mechanisms are mainly intrinsic. On the contrary, the potentially pathogenic isolates presented a broad diversity of acquired antibiotic resistance genes towards different antibiotic classes, especially β-lactams, aminoglycosides, and fluoroquinolones. All these bacteria showed multiple β-lactamase-encoding genes, some with carbapenemase activity, such as the bla_KPC-type genes found in the Enterobacteriaceae isolates. The antibiotic susceptibility testing assays performed on these isolates also revealed that all had a multi-resistance phenotype, which indicates that the acquired resistance is their major antibiotic resistance mechanism. In conclusion, the two bacterial groups have distinct resistance mechanisms, which suggest that the antibiotic resistance in the environment can be a more complex problematic than that generally assumed. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Wastewater and Its Treatment)

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14 pages, 996 KiB

Open AccessEditor’s ChoiceReview

Old and New Beta-Lactamase Inhibitors: Molecular Structure, Mechanism of Action, and Clinical Use

by Davide Carcione, Claudia Siracusa, Adela Sulejmani, Valerio Leoni and Jari Intra

Antibiotics 2021, 10(8), 995; https://doi.org/10.3390/antibiotics10080995 - 17 Aug 2021

Cited by 65 | Viewed by 16240

Abstract

The β-lactams have a central place in the antibacterial armamentarium, but the increasing resistance to these drugs, especially among Gram-negative bacteria, is becoming one of the major threats to public health worldwide. Treatment options are limited, and only a small number of novel [...] Read more.

The β-lactams have a central place in the antibacterial armamentarium, but the increasing resistance to these drugs, especially among Gram-negative bacteria, is becoming one of the major threats to public health worldwide. Treatment options are limited, and only a small number of novel antibiotics are in development. However, one of the responses to this threat is the combination of β-lactam antibiotics with β-lactamase inhibitors, which are successfully used in the clinic for overcoming resistance by inhibiting β-lactamases. The existing inhibitors inactivate most of class A and C serine β-lactamases, but several of class D and B (metallo-β-lactamase) are resistant. The present review provides the status and knowledge concerning current β-lactamase inhibitors and an update on research efforts to identify and develop new and more efficient β-lactamase inhibitors. Full article

(This article belongs to the Special Issue Antibiotic Use in Clinical Infection: How to Reinvent Old Molecules and How to Squeeze Out New Ones)

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14 pages, 1144 KiB

Open AccessEditor’s ChoiceReview

MALDI-TOF Mass Spectrometry Technology as a Tool for the Rapid Diagnosis of Antimicrobial Resistance in Bacteria

by Eun-Jeong Yoon and Seok Hoon Jeong

Antibiotics 2021, 10(8), 982; https://doi.org/10.3390/antibiotics10080982 - 14 Aug 2021

Cited by 49 | Viewed by 8899

Abstract

Species identification by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a routine diagnostic process for infectious diseases in current clinical settings. The rapid, low-cost, and simple to conduct methodology is expanding its application in clinical microbiology laboratories to diagnose the [...] Read more.

Species identification by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a routine diagnostic process for infectious diseases in current clinical settings. The rapid, low-cost, and simple to conduct methodology is expanding its application in clinical microbiology laboratories to diagnose the antimicrobial resistance (AMR) in microorganisms. Primarily, antimicrobial susceptibility testing is able to be carried out either by comparing the area under curve of MALDI spectra of bacteria grown in media with antimicrobial drugs or by identifying the shift peaks of bacteria grown in media including ¹³C isotope with antimicrobial drugs. Secondly, the antimicrobial resistance is able to be determined through identifying (i) the antimicrobial-resistant clonal groups based on the fingerprints of the clone, (ii) the shift peak of the modified antimicrobial drug, which is inactivated by the resistance determinant, (iii) the shift peak of the modified antimicrobial target, (iv) the peak specific for the antimicrobial determinant, and (v) the biomarkers that are coproduced proteins with AMR determinants. This review aims to present the current usage of the MALDI-TOF MS technique for diagnosing antimicrobial resistance in bacteria, varied approaches for AMR diagnostics using the methodology, and the future applications of the methods for the accurate and rapid identification of AMR in infection-causing bacterial pathogens. Full article

(This article belongs to the Special Issue Rapid Diagnostics of the Antimicrobial Resistance)

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12 pages, 2815 KiB

Open AccessEditor’s ChoiceArticle

A Repeated State of Acidification Enhances the Anticariogenic Biofilm Activity of Glass Ionomer Cement Containing Fluoro-Zinc-Silicate Fillers

by Traithawit Naksagoon, Shoji Takenaka, Ryoko Nagata, Maki Sotozono, Tatsuya Ohsumi, Takako Ida, Naoki Edanami, Takeyasu Maeda and Yuichiro Noiri

Antibiotics 2021, 10(8), 977; https://doi.org/10.3390/antibiotics10080977 - 13 Aug 2021

Cited by 5 | Viewed by 2827

Abstract

This study aimed to evaluate the anticariogenic biofilm activity of a novel zinc-containing glass ionomer cement, Caredyne Restore (CR), using a flow-cell system that reproduces Stephan responses. Streptococcus mutans biofilms were cultured on either CR or hydroxyapatite (HA) discs mounted on a modified [...] Read more.

This study aimed to evaluate the anticariogenic biofilm activity of a novel zinc-containing glass ionomer cement, Caredyne Restore (CR), using a flow-cell system that reproduces Stephan responses. Streptococcus mutans biofilms were cultured on either CR or hydroxyapatite (HA) discs mounted on a modified Robbins device. The media were allowed to flow at a speed of 2 mL/min for 24 h while exposed to an acidic buffer twice for 30 min to mimic dietary uptake. Acid exposure enhanced biofilm inhibition in the CR group, which showed 2.6 log CFU/mm² in viable cells and a 2 log copies/mL reduction in total cells compared to the untreated group after 24 h of incubation, suggesting enhanced anticariogenic activity due to the release of fluoride and zinc ions. However, there was no difference in the number of viable and total cells between the two experimental groups after 24 h of incubation in the absence of an acidic environment. The anticariogenic biofilm activity of CR occurs in acidic oral environments, for example in the transient pH drop following dietary uptake. CR restorations are recommended in patients at high risk of caries due to hyposalivation, difficulty brushing, and frequent sugar intake. Full article

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8 pages, 677 KiB

Open AccessEditor’s ChoicePerspective

Biosynthetic Potential of Streptomyces Rationalizes Genome-Based Bioprospecting

by Balasubramanian Cibichakravarthy and Polapass Arul Jose

Antibiotics 2021, 10(7), 873; https://doi.org/10.3390/antibiotics10070873 - 19 Jul 2021

Cited by 6 | Viewed by 3850

Abstract

Streptomyces are the most prolific source of structurally diverse microbial natural products. Advancing genome-based analysis reveals the previously unseen potential of Streptomyces to produce numerous novel secondary metabolites, which allows us to take natural product discovery to the next phase. However, at present [...] Read more.

Streptomyces are the most prolific source of structurally diverse microbial natural products. Advancing genome-based analysis reveals the previously unseen potential of Streptomyces to produce numerous novel secondary metabolites, which allows us to take natural product discovery to the next phase. However, at present there is a huge disproportion between the rate of genome reports and discovery of new compounds. From this perspective of harnessing the enduring importance of Streptomyces, we discuss the recent genome-directed advancements inspired by hidden biosynthetic wealth that provide hope for future antibiotics. Full article

(This article belongs to the Special Issue Discovery and Biosynthesis of Novel Antibiotic from Streptomyces)

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30 pages, 6960 KiB

Open AccessEditor’s ChoiceArticle

A Fine-Tuned Lipophilicity/Hydrophilicity Ratio Governs Antibacterial Potency and Selectivity of Bifurcated Halogen Bond-Forming NBTIs

by Anja Kolarič, Maja Kokot, Martina Hrast, Matjaž Weiss, Irena Zdovc, Jurij Trontelj, Simon Žakelj, Marko Anderluh and Nikola Minovski

Antibiotics 2021, 10(7), 862; https://doi.org/10.3390/antibiotics10070862 - 15 Jul 2021

Cited by 15 | Viewed by 6327

Abstract

Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against [...] Read more.

Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential. Full article

(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)

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25 pages, 465 KiB

Open AccessEditor’s ChoiceReview

Role of RND Efflux Pumps in Drug Resistance of Cystic Fibrosis Pathogens

by Viola Camilla Scoffone, Gabriele Trespidi, Giulia Barbieri, Samuele Irudal, Elena Perrin and Silvia Buroni

Antibiotics 2021, 10(7), 863; https://doi.org/10.3390/antibiotics10070863 - 15 Jul 2021

Cited by 25 | Viewed by 5468

Abstract

Drug resistance represents a great concern among people with cystic fibrosis (CF), due to the recurrent and prolonged antibiotic therapy they should often undergo. Among Multi Drug Resistance (MDR) determinants, Resistance-Nodulation-cell Division (RND) efflux pumps have been reported as the main contributors, due [...] Read more.

Drug resistance represents a great concern among people with cystic fibrosis (CF), due to the recurrent and prolonged antibiotic therapy they should often undergo. Among Multi Drug Resistance (MDR) determinants, Resistance-Nodulation-cell Division (RND) efflux pumps have been reported as the main contributors, due to their ability to extrude a wide variety of molecules out of the bacterial cell. In this review, we summarize the principal RND efflux pump families described in CF pathogens, focusing on the main Gram-negative bacterial species (Pseudomonas aeruginosa, Burkholderia cenocepacia, Achromobacter xylosoxidans, Stenotrophomonas maltophilia) for which a predominant role of RND pumps has been associated to MDR phenotypes. Full article

(This article belongs to the Special Issue The Structural and Functional Study of Efflux Pumps Belonging to the RND Transporters Family from Gram-Negative Bacteria)

9 pages, 482 KiB

Open AccessEditor’s ChoiceArticle

National Facilitators and Barriers to the Implementation of Incentives for Antibiotic Access and Innovation

by Christine Årdal, Yohann Lacotte, Suzanne Edwards, Marie-Cécile Ploy and on behalf of the European Union Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI)

Antibiotics 2021, 10(6), 749; https://doi.org/10.3390/antibiotics10060749 - 21 Jun 2021

Cited by 6 | Viewed by 3818

Abstract

Prominent reports have assessed the challenges to antibiotic innovation and recommended implementing “pull” incentives, i.e., mechanisms that give increased and predictable revenues for important, marketed antibiotics. We set out to understand countries’ perceptions of these recommendations, through frank and anonymous dialogue. In 2019 [...] Read more.

Prominent reports have assessed the challenges to antibiotic innovation and recommended implementing “pull” incentives, i.e., mechanisms that give increased and predictable revenues for important, marketed antibiotics. We set out to understand countries’ perceptions of these recommendations, through frank and anonymous dialogue. In 2019 and 2020, we performed in-depth interviews with national policymakers and antibiotic resistance experts in 13 countries (ten European countries and three non-European) for a total of 73 individuals in 27 separate interviews. Interviewees expressed high-level support for antibiotic incentives in 11 of 13 countries. There is recognition that new economic incentives are needed to maintain a reliable supply to essential antibiotics. However, most countries are uncertain which incentives may be appropriate for their country, which antibiotics should be included, how to implement incentives, and how much it will cost. There is a preference for a multinational incentive, so long as it is independent of national pricing, procurement, and reimbursement processes. Nine countries indicated a preference for a model that ensures access to both existing and new antibiotics, with the highest priority for existing antibiotics. Twelve of thirteen countries indicated that shortages of existing antibiotics is a serious problem. Since countries are skeptical about the public health value of many recently approved antibiotics, there is a mismatch regarding revenue expectations between policymakers and antibiotic innovators. This paper presents important considerations for the design and implementation of antibiotic pull mechanisms. We also propose a multinational model that appears to match the needs of both countries and innovators. Full article

(This article belongs to the Section The Global Need for Effective Antibiotics)

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16 pages, 8515 KiB

Open AccessEditor’s ChoiceArticle

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

by Emmanuela Adjei-Sowah, Yue Peng, Jason Weeks, Jennifer H. Jonason, Karen L. de Mesy Bentley, Elysia Masters, Yugo Morita, Gowrishankar Muthukrishnan, Philip Cherian, X. Eric Hu, Charles E. McKenna, Frank H. Ebetino, Shuting Sun, Edward M. Schwarz and Chao Xie

Antibiotics 2021, 10(6), 732; https://doi.org/10.3390/antibiotics10060732 - 17 Jun 2021

Cited by 17 | Viewed by 5138

Abstract

The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” [...] Read more.

The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA. Full article

(This article belongs to the Special Issue Development of Antimicrobial Biomaterials and Natural Alternatives against Biofilms and Implant-Related Infections)

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12 pages, 560 KiB

Open AccessEditor’s ChoicePerspective

Basics for Improved Use of Phages for Therapy

by Philip Serwer, Elena T. Wright, Jorge De La Chapa and Cara B. Gonzales

Antibiotics 2021, 10(6), 723; https://doi.org/10.3390/antibiotics10060723 - 16 Jun 2021

Cited by 13 | Viewed by 4096

Abstract

Blood-borne therapeutic phages and phage capsids increasingly reach therapeutic targets as they acquire more persistence, i.e., become more resistant to non-targeted removal from blood. Pathogenic bacteria are targets during classical phage therapy. Metastatic tumors are potential future targets, during use of drug delivery [...] Read more.

Blood-borne therapeutic phages and phage capsids increasingly reach therapeutic targets as they acquire more persistence, i.e., become more resistant to non-targeted removal from blood. Pathogenic bacteria are targets during classical phage therapy. Metastatic tumors are potential future targets, during use of drug delivery vehicles (DDVs) that are phage derived. Phage therapy has, to date, only sometimes been successful. One cause of failure is low phage persistence. A three-step strategy for increasing persistence is to increase (1) the speed of lytic phage isolation, (2) the diversity of phages isolated, and (3) the effectiveness and speed of screening phages for high persistence. The importance of high persistence-screening is illustrated by our finding here of persistence dramatically higher for coliphage T3 than for its relative, coliphage T7, in murine blood. Coliphage T4 is more persistent, long-term than T3. Pseudomonas chlororaphis phage 201phi2-1 has relatively low persistence. These data are obtained with phages co-inoculated and separately assayed. In addition, highly persistent phage T3 undergoes dispersal to several murine organs and displays tumor tropism in epithelial tissue (xenografted human oral squamous cell carcinoma). Dispersal is an asset for phage therapy, but a liability for phage-based DDVs. We propose increased focus on phage persistence—and dispersal—screening. Full article

(This article belongs to the Special Issue Phage Therapy to Control Pathogenic Bacteria)

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17 pages, 5061 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

by Hang Thi Nguyen, Mahmud T. Morshed, Daniel Vuong, Andrew Crombie, Ernest Lacey, Sanjay Garg, Hongfei Pi, Lucy Woolford, Henrietta Venter, Stephen W. Page, Andrew M. Piggott, Darren J. Trott and Abiodun D. Ogunniyi

Antibiotics 2021, 10(6), 727; https://doi.org/10.3390/antibiotics10060727 - 16 Jun 2021

Cited by 1 | Viewed by 4010

Abstract

Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of [...] Read more.

Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes. Full article

(This article belongs to the Section Novel Antimicrobial Agents)

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14 pages, 605 KiB

Open AccessEditor’s ChoiceArticle

Impact of an Antimicrobial Stewardship Program on the Incidence of Carbapenem Resistant Gram-Negative Bacilli: An Interrupted Time-Series Analysis

by Teresa López-Viñau, Germán Peñalva, Lucrecia García-Martínez, Juan José Castón, Montserrat Muñoz-Rosa, Ángela Cano, Manuel Recio, José Miguel Cisneros, Elena Pérez-Nadales, José Rumbao Aguirre, Elena García-Martínez, Inmaculada Salcedo, José Ramón del Prado, Carmen de la Fuente, Luis Martínez-Martínez, Irene Gracia-Ahufinger and Julián Torre-Cisneros

Antibiotics 2021, 10(5), 586; https://doi.org/10.3390/antibiotics10050586 - 16 May 2021

Cited by 14 | Viewed by 5017

Abstract

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of [...] Read more.

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect −83.51%; 95% CI −87.23 to −79.79). The incidence density of CR-GNB decreased by −0.915 cases per 1000 occupied bed days (95% CI −1.743 to −0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of −91.15% (95% CI −105.53 to −76.76) and −89.93% (95% CI −107.03 to −72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates. Full article

(This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship)

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